A longitudinal study will be conducted of clinical presentation, immune phenotype, gene expression and virus infection among ME/CFS patients and MS and population controls frequency-matched by geographical area of residence, age-group (within 5 years), and sex. Clinical samples will be collected for studies of NK cell function virology (herpesvirus infection), and gene expression and for banking as a resource for future ME/CFS research. Hypothesis: ME/CFS is associated with immune dysfunction, which results from - or predisposes to - herpesvirus infections. Immune dysfunction will present as alterations in NK cell function that may lead to, or result from, alterations in cytokine production and altere expression of diverse immune-associated genes. Finally, we predict that the ME/CFS immune phenotype may fluctuate over time and in association with clinical presentation and that the majority of patients clinically characterized as having ME/CFS will show a biosignature distinct from that of controls, and that further alterations will be seen during episodes of clinical exacerbation. Activities and objectives: i) Collect clinical and other data and venous blood samples at baseline and 6 months or at another time during the 6-month follow-up period when there is a perceived significant deterioration in symptoms; ii) Analyze blood samples for NK cell phenotype and function; iii) Screen samples for evidence of herpesvirus infection and viral load, focusing on Epstein Barr virus (EBV), cytomegalovirus (CMV), and human herpesvirus-6 (HHV-6); iv) Describe clinical phenotype and fluctuations over time; v) Correlate the presence of symptoms and severity with markers of virus activity and immune function; vi) Investigate gene expression profiles associated with ME/CFS and how they vary in relation to changes in disease severity, virus activity, NK cell function, and other markers of immune function; and vii) Securely store blood samples from patients and controls, anonymously linked to clinical and other data, as an open resource for researchers to conduct ethically-approved studies of ME/CFS. Recruitment: 150 ME/CFS cases (50 severe, 100 non-severe), 75 MS controls, and 75 healthy controls will be recruited. For immunology and virology, 100 cases, 50 MS controls, and 50 healthy controls will be sampled at 2 time points. For gene expression, we will analyze 50 ME/CFS cases, 25 MS and 25 healthy controls, each at recruitment and one follow-up. Cases will be selected from UK ME/CFS Disease Register and NHS ME/CFS specialty and primary care services in London and Norfolk, Suffolk, and Great Yarmouth and Waveney, UK; MS controls via the NHS; and healthy controls will be identified by ME/CFS patients (excluding blood relatives) or GPs. Outcomes: Identification of putative biomarkers for diagnosis, severity, and prognosis of ME/CFS, which can be evaluated in larger (ideally prospective) future studies. In the long term, identification of robust biomarkers will allow clinicians to correlate ME/CFS phenotype (including clinical presentation, genetic, immune, and viral markers) with disease severity and prognosis and may reveal new options for interventions research.